The long-term goal of this study is to understand immune tolerance to oral bacteria in the context of periodontal inflammation. In the healthy individuals, immune tolerance seems to be developed to these bacteria, similar to the intestinal situation where tolerance is induced to commensal bacteria as well as dietary antigens. Preliminary results demonstrated that oral infection with Actinobacillus actinomyceremcomitans (Aa) induced immunological tolerance. Passive induction of Th1-immune response to the bacteria resulted in inflammatory bone resorption by RANKL expressing Th1-type cells. In order to elucidate the mechanism of tolerance to oral commensal bacteria, I propose to study the role of such tolerance in preventing inflammatory bone resorption in an experimental animal model. It is well documented that IL-10 is associated with induction of tolerance. The significance of IL-l0 in the induction of tolerance to oral bacteria will be studied in a mouse model of periodontal disease. We will further search the influence of vasoactive intestinal protein (VIP) on the oral immune system in association with tolerance development. VIP is produced by lymphocytes and possess immune suppressive function, demonstrated by induction of IL- 10 and down-regulation of proinflammatory cytokine production by macrophages. Among at least 20 of neuropeptides that are produced by lymphocytes, only VIP and pituitary adenylate cyclase-activating polypeptide (PACAP) which share a family of receptors, exert anti-inflammatory functions. Although VIP has been detected in saliva and produced by gingival epithelial cells, the significance of VIP in the course of tolerance induction in the oral cavity is totally unknown. Therefore, the role of VIP on tolerance to oral bacteria and therapeutic application of VIP will be examined in the mouse model. Our goal is to characterize the tolerance to the oral bacteria in association with lymphocyte mediated periodontal inflammation. This goal will be pursued under the following specific aims.